Researchers at Johns Hopkins have discovered that the Notch protein helps human embryonic stem cells 'decide' their own fate, a finding which may eventually be useful in programming cells for the development of stem cell therapies. Their results are reported in the May 2008 issue of Cell Stem Cell.
Human embryonic stem cells (hESCs) receive signals from neighboring cells instructing them either to grow more of themselves or become other cell types, including the three types that make up the developing embryo or type that becomes the placenta. Researchers are just beginning to understand the many signals involved in committing hESCs to different fates.
"If you can understand the mechanisms involved in lineage commitment, basically you can open the door to a lot of things," says Xiaobing Yu, M.D., a research associate at the Institute for Cell Engineering at Johns Hopkins. Such an understanding would help scientists program hESCs to replace cells that patients lose as a result of injury or disease.
Yu and his colleagues have made one initial step towards this goal by clarifying the often disputed fate-determining role of one protein found on the surface of hESCs' Notch.
In an effort to figure out Notch's role in determining stem cell fate, the researchers first grew hESCs in a laboratory culture dish lined with a feeding layer of embryonic mouse cells, which encourage hESCs to replicate. They examined the cells and found very few stem cells contained active Notch. When the researchers chemically prevented the protein from being turned on, they found that a greater number of hESCs self-renewed and made more of themselves suggesting that Notch is required for differentiation and the lack thereof helps maintain cells in an undifferentiated state.
The researchers then prodded hESCs to differentiate. While Notch stayed inactive in self-renewing hESCs, its activity spiked in cells that started differentiating, suggesting that Notch somehow was involved in cell differentiation. The question was: Does the protein cause differentiation or is it turned on as a result?
In order to figure this out, the researchers stimulated hESCs to differentiate and in the same cells prevented Notch from being turned on. Without it, these cells grew into cells that become the placenta, suggesting to the researchers that early placental development does not require Notch. Without Notch, these cells did not ever grow into any of the three cell types that make up a developing human embryo. Therefore, it must be required for differentiation into embryonic cell types, the researchers concluded.